Cationic steroid antibacterial compounds and method for producing cationic steroid antibacterial compounds

Abstract

A structure of formula I, II or III, JPEG2023527736000019.jpg97170R1~R 18 At least one of (e.g., R3, R7 and R 12 ) is a cationic steroid antibacterial (CSA) compound having the structure: linked to a steroidal backbone by a urethane group, or a salt thereof. R1~R 18 At least one of (e.g., R3, R7 and R 12 ) is the following uretanyl structure: -O-(C=O)-NR 19 R 20 and R 19 and R 20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aminoalkyl, aminoalkenyl, aminoalkynyl, or aminoaryl, with the proviso that R 19 or R 20 At least one of the groups contains an amino group (e.g., R 19 is hydrogen and R 20 is (C2-C6) aminoalkyl). R 18 has the following structure: -R 21 -(C=O)-NR 22 R 23 and R 21 is omitted or is alkyl, alkenyl, alkynyl, or aryl, and R 22 and R 23 is hydrogen, alkyl, alkenyl, alkynyl, or aryl, with the proviso that R 22 or R 23 At least one of these is not hydrogen.

Description

Technical Field

[0001] The present invention relates to a cationic steroid antibacterial (CSA) compound having a urethane bond, a CSA compound, and a method for producing a CSA compound having a urethane bond.

Background Art

[0002] Antibacterial peptides have been found in organisms ranging from mammals to amphibians, insects, and plants. The ubiquity of antibacterial peptides has been used as evidence that bacterial resistance to these compounds does not easily occur. Furthermore, considering the diverse sequences of antibacterial peptides in various organisms, it is clear that antibacterial peptides have evolved independently multiple times. Therefore, antibacterial peptides appear to be one of the main means by which nature controls bacterial growth. For example, endogenous antibacterial peptides such as human cathelicidin LL-37 play a key role in innate immunity. LL-37 is found in airway mucus and is thought to be important for controlling bacterial growth in the lung. However, clinical use of antibacterial peptides presents important challenges including the relatively high cost of producing peptide-based therapeutics, the sensitivity of peptides to proteases produced by the host and pathogenic microorganisms, and the inactivation of antibacterial peptides by proteins and DNA in the lung mucosa.

[0003] An attractive means of utilizing the antibacterial activity of antibacterial peptides without incurring the problems described above is to develop non-peptidic mimics of antibacterial peptides that exhibit a similar broad spectrum of antibacterial activity using the same or similar mechanisms of action. Non-peptidic mimics can be synthesized at low cost and may have increased stability against proteolysis. Furthermore, control of water solubility and charge density can be used to control binding to proteins and DNA in the lung mucosa.

[0004] Using examples of more than 1,600 known antimicrobial peptides, structural features common to the known antimicrobial peptides can be classified. Although the primary sequences of these peptides vary considerably, the forms used by the majority are similar. Those adopting an α-helix conformation have hydrophobic side chains juxtaposed on one face of the helix and cationic (positively charged) side chains on the opposite face. A similar form is seen in antimicrobial peptides forming a β-sheet structure, with hydrophobic side chains on one face of the sheet and cationic side chains on the other face.

[0005] Examples of small molecules, non-peptidic mimics of antimicrobial peptides include the steroid compound known as "ceragenin", and an example of a steroid compound is "CSA-13" which can reproduce the amphiphilic form of antimicrobial peptides. The remaining problem is that in many cases, the production of CSA compounds requires complex multi-step continuous reactions. In the production of CSA compounds, the cost increases and the overall product yield decreases with each additional reaction. Therefore, there remains a need to identify CSA compounds that are easy and inexpensive to produce but have desirable antibacterial, anti-inflammatory, and other desirable properties and effects. SUMMARY OF THE INVENTION

[0006] Disclosed herein are novel types of cationic steroid antimicrobials (CSA) compounds having urethane groups linking one or more side chains to a sterol backbone. The urethane-linked CSA compounds are easy and inexpensive to produce but still possess desirable antibacterial, anti-inflammatory, and other desirable properties.

[0007] The CSA compounds, including salts of the CSA compounds, disclosed herein may have the structure of Formula I, II or I II, which structure has a fused-ring sterol backbone, and at least one of R1 to R

Chemical formula

[0008] In an embodiment, R1 to R 18 At least one of at least one, preferably R3, R7 and R 12 At least one of them has the following urethanyl structure, -O-(C=O)-NR 19 R 20 and may have R 19 and R 20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aminoalkyl, aminoalkenyl, aminoalkynyl, and aminoaryl, provided that R 19 or R 20 At least one of them contains an amino group, preferably R 19 is hydrogen and R 20 is (C2-C6) aminoalkyl.

[0009] In an embodiment, R 18 has the following structure, -R 21 -(C=O)-NR 22 R 23 and may have R 21 is omitted or is alkyl, alkenyl, alkynyl, or aryl, and R 22 and R 23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and aryl, provided that R 22 or R 23 At least one of them is not hydrogen.

[0010] Non-limiting examples of CSA compounds in which at least one of R3, R7 and R 12 is linked to the sterol skeleton by a urethane bond are CSA-255, CSA-256, CSA-257, CSA-258, and salts thereof.

Chemical formula

[0011] In an embodiment, the method for producing a CSA compound having a urethane bond disclosed herein optionally reacts or protects the acidic group of cholic acid in one or more steps by forming an amide at the C24 position or the like to form R 18 and (2) reacting at least one of the hydroxyl groups at the C3, C7, and C12 positions of cholic acid in one or more steps to form a urethane bond, wherein the urethane bond binds at least one of R3, R7, and R 12 to the steroid backbone to obtain the desired CSA compound.

[0012] Advantages of the CSA compounds disclosed herein include equivalent and / or improved antibacterial activity, anti-inflammatory activity, and other desired properties compared to existing CSA compounds, and / or simplified synthesis of CSA compounds and / or intermediate CSA compounds compared to existing synthetic routes, but are not limited thereto.

[0013] Additional features and advantages will be described in part in the following description, become apparent in part from the description, or may be learned by practice of the embodiments disclosed herein. It is to be understood that both the foregoing summary and the following detailed description are exemplary and not restrictive of the embodiments disclosed and claimed herein.

Best Mode for Carrying Out the Invention

[0014] Disclosed herein are new types of cationic steroid antibacterial (CSA) compounds having urethane functional groups that link one or more side chains to a steroid backbone. The urethane-linked CSA compounds are easy and inexpensive to manufacture, yet still possess desirable antibacterial, anti-inflammatory, and other desirable properties.

[0015] Definitions Without limitation, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 Any "R" group, such as those of R, R, R, R, R, R, and R, represents a substituent that can be attached to the steroid skeleton. Unless otherwise specified, the R group may be substituted or unsubstituted.

[0016] As used herein, "ring" may be heterocyclic or carbocyclic. "Saturated" means a ring in which each atom is hydrogenated or substituted so that the valence of each atom is satisfied. "Unsaturated" means a ring in which the valence of each atom of the ring may not be satisfied by hydrogen or another substituent. For example, adjacent carbon atoms of a fused ring can be bonded to each other by a double bond. Unsaturation can also include removing at least one of the following pairs, such as R5 and R9; R8 and R; and R and R, and completing the valence of the carbon atoms of the ring at the positions where these are removed with double bonds. 10 ; and R 13 and R 14 and completing the valence of the carbon atoms of the ring at the positions where these are removed with double bonds.

[0017] When a group is "substituted", it may be substituted with one, two, three or more of the indicated substituents, the substituents may be the same or different, and each replaces a hydrogen atom. When no substituents are indicated, the indicated "substituted" group is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, acylalkyl, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen (e.g., F, Cl, Br, and I), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, amino, monosubstituted amino group, and disubstituted amino group, R a O(CH2) m O-, R b (CH2) n O-, R c C(O)O(CH2) p O-, and may be substituted with one or more groups independently selected individually from the protected derivatives of these groups. The substituents may be attached to the group at multiple attachment points. For example, two attachment points of an aryl group may be substituted with a heteroaryl group to form a fused polycyclic aromatic ring system. Biphenyl and naphthalene are two examples of an aryl group substituted with a second aryl group. A group that is not explicitly indicated as substituted or unsubstituted may be considered to be either substituted or unsubstituted.

[0018] "a" and "b" are integers, "C a " or "C a ~C bThe term "a to b" means the number of carbon atoms in an alkyl group, alkenyl group, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heteroaryl group, or heteroaricyclic group. That is, this alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring, aryl ring, heteroaryl ring, or heteroaricyclic ring can contain carbon atoms from "a" to "b". Thus, for example, "C1-C4 alkyl" refers to all alkyl groups having 1 to 4 carbon atoms, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2 CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified for an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heteroaryl group, or heteroaricyclic group, the broadest scope described in these definitions shall be assumed.

[0019] "Urethanil" means "-O-(C=O)-NR 19 R 20 ", as more fully defined herein.

[0020] "Alkyl" means a straight-chain or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 25 carbon atoms (whenever a numerical range appears in this specification, the numerical range such as "1 to 25" means each integer within the given range. For example, "1 to 25 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 25 carbon atoms, provided that this definition also applies even if there is a term "alkyl" for which no numerical range is specified). The alkyl group may also be a medium-sized alkyl having 1 to 15 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound may be designated as "C4" or "C1-C4 alkyl" or a similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. The alkyl group may be substituted or unsubstituted.

[0021] "Alkenyl" means an alkyl group containing one or more double bonds in a straight-chain or branched hydrocarbon chain. The alkenyl group may have 2 to 25 carbon atoms (whenever a numerical range appears in this specification, the numerical range such as "2 to 25" means each integer within the given range. For example, "2 to 25 carbon atoms" means that the alkenyl group may consist of 25 or fewer carbon atoms such as 2, 3, or 4 carbon atoms, provided that this definition also applies even if there is a term "alkenyl group" for which no numerical range is specified). The alkenyl group may also be a medium-sized alkenyl having 2 to 15 carbon atoms. The alkenyl group may also be a lower alkenyl having 1 to 6 carbon atoms. The alkenyl group of a compound may be designated as "C4" or "C2-C4 alkenyl" or a similar designation. The alkenyl group may be unsubstituted or substituted.

[0022] "Alkynyl" means an alkyl group containing one or more triple bonds in a straight-chain or branched hydrocarbon chain. The alkynyl group may have 2 to 25 carbon atoms (whenever a numerical range appears in this specification, the numerical range such as "2 to 25" means each integer within the given range. For example, "2 to 25 carbon atoms" means that the alkynyl group may consist of 25 or fewer carbon atoms such as 2, 3, or 4 carbon atoms, provided that this definition also applies even if there is a term "alkynyl group" for which no numerical range is specified). The alkynyl group may also be a medium-sized alkynyl having 2 to 15 carbon atoms. The alkynyl group may also be a lower alkynyl having 2 to 6 carbon atoms. The alkynyl group of a compound may be designated as "C4" or "C2-C4 alkynyl" or a similar designation. The alkynyl group may be unsubstituted or substituted.

[0023] "Aryl" means a monocyclic or polycyclic aromatic ring system of a carbocyclic ring (all carbon) having a π-electron system that is completely delocalized throughout all rings (including a fused ring system in which two carbocyclic rings share a chemical bond). The number of carbon atoms in the aryl group may vary. For example, the aryl group is C6-C14 An aryl group, C6-C 10 It can be an aryl group, or a C6 aryl group (however, C6-C 10 The definition of aryl also applies even if there is "aryl" when no numerical range is specified.). Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0024] "Aralkyl" and "aryl(alkyl)" mean an aryl group bonded via a lower alkylene group as a substituent. The aralkyl group may have 6 to 20 carbon atoms (whenever a numerical range appears in this specification, a numerical range such as "6 to 20" means each integer within the given range. For example, "6 to 20 carbon atoms" means that the aralkyl group may consist of 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, etc., up to 20 carbon atoms, provided that this definition also applies even if there is the term "aralkyl group" for which no numerical range is specified). The lower alkylene group and aryl group of aralkyl may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0025] "Lower alkylene group" means a C1-C tether group such as a -CH2- tether group 25 A straight-chain alkyl tether group that forms a bond connecting molecular fragments via the carbon atoms at the ends of the molecular fragments. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). The lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group with substituents described in the definition of "substituted".

[0026] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon ring system that is completely saturated (having no double or triple bonds). When consisting of two or more rings, the rings may be fused together. The cycloalkyl group may contain 3 to 10 atoms in the ring or may contain 3 to 8 atoms in the ring. The cycloalkyl group may be unsubstituted or substituted. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0027] "Cycloalkenyl" means a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that, in the case of multiple double bonds, they cannot form a completely delocalized π - electron system throughout all the rings (otherwise, the group would be an "aryl" as defined herein). When consisting of two or more rings, the rings may be fused together. The cycloalkenyl group may be unsubstituted or substituted.

[0028] "Cycloalkynyl" means a monocyclic or polycyclic hydrocarbon ring system containing one or more triple bonds in at least one ring. When there are multiple triple bonds, they cannot form a completely delocalized π - electron system throughout all the rings. When composed of two or more rings, the rings may be fused together. The cycloalkynyl group may be unsubstituted or substituted.

[0029] "Alkoxy" or "alkyloxy" means the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl as defined above. A non - limiting list of alkoxys is methoxy, ethoxy, n - propoxy, 1 - methylethoxy (isopropoxy), n - butoxy, iso - butoxy, sec - butoxy, and tert - butoxy. The alkoxy may be substituted or unsubstituted.

[0030] "Acyl" means bonded through a carbonyl group such as -(C = O)-R as a substituent It refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl. Examples include formyl, acetyl, propanoyl, benzoyl, and acryloyl. The acyl group may be substituted or unsubstituted.

[0031] "Alkoxyalkyl" or "alkyloxyalkyl" means an alkoxy group as a substituent bonded via a lower alkylene group. Examples include alkyl-O-alkyl- and alkoxy-alkyl-, and the terms alkyl and alkoxy are defined herein.

[0032] "Hydroxyalkyl" means an alkyl group in which one or more hydrogen atoms are substituted with hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. The hydroxyalkyl may be substituted or unsubstituted.

[0033] "Haloalkyl" means an alkyl group in which one or more hydrogen atoms are substituted with halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Examples include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, etc. The haloalkyl may be substituted or unsubstituted.

[0034] "Amino" means "-NH2".

[0035] "Hydroxy" means "-OH".

[0036] "Cyano" means "-CN".

[0037] "Carbonyl" or "oxo" means "-C=O".

[0038] "Azide" means "-N3".

[0039] "Aminoalkyl" means an amino group as a substituent bonded via a lower alkylene group. Examples include H2N-alkyl- having the term alkyl defined herein.

[0040] "Alkylcarboxyalkyl" means an alkyl group bonded as a substituent to a carboxy group, and an alkyl group bonded as a substituent to the carboxy group. Examples include alkyl-(C=O)-O-alkyl- and alkyl-O-(C=O)-alkyl-, and the term alkyl is defined herein.

[0041] "Alkylaminoalkyl" means an alkyl group, an amino group bonded as a substituent to the alkyl group, and an alkyl group bonded as a substituent to the amino group. Examples include alkyl-NH-alkyl- having the term alkyl defined herein.

[0042] "Dialkylaminoalkyl" and "di(alkyl)aminoalkyl" mean an amino group bonded as a substituent to an alkyl group, and two alkyl groups bonded as substituents to the amino group, respectively. Examples include

Chemical formula

[0043] "Alkylaminoalkylamino" means an amino group, an alkyl group bonded as a substituent to the amino group, an amino group bonded as a substituent to the alkyl group, and an alkyl group bonded as a substituent to the amino group. Examples include alkyl-NH-alkyl-NH- having the term alkyl defined herein.

[0044] "Alkylaminoalkylaminoalkyl" means an alkyl group having an amino group bonded thereto as a substituent, an alkyl group bonded thereto as a substituent, an amino group bonded thereto as a substituent, and an alkyl group bonded thereto as a substituent. Examples include alkyl-NH-alkyl-NH-alkyl- having the term alkyl defined herein.

[0045] "Arylaminoalkyl" means an amino group bonded to an alkyl group as a substituent and an aryl group bonded as a substituent. Examples include aryl-NH-alkyl- having the terms aryl and alkyl defined herein.

[0046] "Aminoalkyloxy" means an amino group bonded to an alkyloxy group as a substituent. Examples include H2N-alkyl-O- and H2N-alkoxy-, where the terms alkyl and alkoxy are defined herein.

[0047] "Aminoalkyloxyalkyl" means an alkyloxy group bonded to an alkyl group as a substituent and an amino group bonded as a substituent. Examples include H2N-alkyl-O-alkyl- and H2N-alkoxy-alkyl-, where the terms alkyl and alkoxy are defined herein.

[0048] "Aminoalkylcarboxy" means an alkyl group bonded to a carboxy group as a substituent and an amino group bonded as a substituent. Examples include H2N-alkyl-(C=O)-O- and H2N-alkyl-O-(C=O)- having the term alkyl defined herein.

[0049] "Aminoalkylaminocarbonyl" means a carbonyl group having an amino group bonded thereto as a substituent, an alkyl group bonded thereto as a substituent, and an amino group bonded thereto as a substituent. Examples include H2N-alkyl-NH-(C=O)- having the term alkyl defined herein.

[0050] "Aminoalkyl carboxamide" means a carbonyl group bonded as a substituent to a certain amino group, an alkyl group bonded as a substituent, and an amino group bonded as a substituent. Examples include H2N-alkyl-(C=O)-NH- and H2N-alkyl-NH-(C=O)- having the term alkyl defined herein.

[0051] "Azidoalkyloxy" means an alkyl-oxy group to which an azido group is bonded as a substituent. Examples include N3-alkyl-O- and N3-alkoxy-, where the terms alkyl and alkoxy are defined herein.

[0052] "Cyanoalkyloxy" means an alkyl-oxy group to which a cyano group is bonded as a substituent. Examples include NC-alkyl-O- and NC-alkoxy-, where the terms alkyl and alkoxy are defined herein.

[0053] "Sulfenyl" means "-SR", where R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl. Sulfenyl may be substituted or unsubstituted.

[0054] "Sulfinyl" means "-(S=O)-R", where R may be the same as defined for sulfenyl. Sulfinyl may be substituted or unsubstituted.

[0055] "Sulfonyl" means "-(S=O)-OR", where R may be the same as defined for sulfonyl. Sulfonyl may be substituted or unsubstituted.

[0056] "O-carboxy" means "R-(C=O)-O-", where R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl as defined herein. O-carboxy may be substituted or unsubstituted.

[0057] "Ester" and "C-carboxy" mean "-(C=O)-OR", where R may be the same as that defined for O-carboxy. Ester and C-carboxy may be substituted or unsubstituted.

[0058] "Thiocarbonyl" means "-(C=S)-R", where R may be the same as that defined for O-carboxy. Thiocarbonyl may be substituted or unsubstituted.

[0059] "Trihalomethanesulfonyl" means "X3CSO2-", where X is halogen.

[0060] "S-sulfonamide" means "-SO2N(RARB)", where RA and RB are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl. S-sulfonamide may be substituted or unsubstituted.

[0061] "N-sulfonamide" means "RSO2N(RA)-", where R and RA are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl. N-sulfonamide may be substituted or unsubstituted.

[0062] "O-carbamyl" means "-O-(C=O)-N(RARB)", where RA and RB are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl. O-carbamyl may be substituted or unsubstituted.

[0063] "N-carbamyl" means "RO-(C=O)-N(RA)-", where R and RA are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic). N-carbamyl may be substituted or unsubstituted.

[0064] "O-thiocarbamyl" means "-O-(C=S)-N(RARB)", where RA and RB are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl. O-thiocarbamyl may be substituted or unsubstituted.

[0065] "N-thiocarbamyl" means "RO-(C=S)-N(RA)-", where R and RA are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl. N-thiocarbamyl may be substituted or unsubstituted.

[0066] "C-amido" means "-(C=O)-N(RARB)," where RA and RB can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. C-amido can be substituted or unsubstituted.

[0067] "N-amido" means "R-(C=O)-N(RA)-", where R and R can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. N-amido can be substituted or unsubstituted.

[0068] "Guanidinoalkyloxy" refers to a guanidinyl group attached as a substituent to an alkyloxy group. Examples include: [ka] and [ka] wherein the terms alkyl and alkoxy are defined herein.

[0069] "Guanidinoalkylcarboxy" refers to a carboxy group that is bonded as a substituent. It refers to a guanidinyl group attached as a substituent to an alkyl group. Examples include: [ka] and [ka] where the term alkyl is defined herein.

[0070] "Quaternary ammonium alkyl carboxy" means a carboxy group to which is attached as a substituent an alkyl group to which is attached as a substituent a quaternized amino group. Examples include

Chemical formula

Chemical formula

[0071] "Halogen atom" and "halogen" mean any one of the radiation-stable atoms listed in column 7 of the periodic table of the elements, such as fluorine, chlorine, bromine, and iodine.

[0072] When the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may contain one or more of the same or different halogens.

[0073] "Amino acid" means any amino acid (both standard and non-standard amino acids), including but not limited to α-amino acids, β-amino acids, γ-amino acids, and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypsi, 2-aminoisobutyric acid, dehydroalanine, γ-aminoisobutyric acid, citrulline, β-alanine, α-ethylglycine, α-propylglycine, and norleucine .

[0074] The "linking group" is a divalent moiety used to link one steroid to another steroid. In multiple embodiments, the linking group is used to link a first CSA to a second CSA (the CSAs may be the same or different). Examples of linking groups include (C1-C 10 ) alkyloxy-(C1-C 10 ) alkyl.

[0075] "P.G.", "protecting group", or "plural protecting groups" means any atom or group of atoms added to a molecule to prevent existing groups within the molecule from undergoing undesired chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be selected to be stable under specific reaction conditions and removable easily at a convenient stage using methodologies known in the art.Non-limiting lists of protecting groups include benzyl, substituted benzyl, alkylcarbonyl and alkoxycarbonyl (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl), arylalkylcarbonyl and arylalkoxycarbonyl (e.g., benzyloxycarbonyl), substituted methyl ethers (e.g., methoxymethyl ether), substituted ethyl ethers, substituted benzyl ethers, tetrahydropyranyl ethers, silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, triisopropylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl, etc.), esters (e.g., benzoate esters, etc.), carbonates (e.g., methoxymethyl carbonate, etc.), sulfonates (e.g., tosylate or mesylate, etc.); acyclic ketals (e.g., dimethyl acetal, etc.); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolane, and those described herein); acyclic acetals; cyclic acetals (e.g., those described herein); acyclic hemiacetals; cyclic hemiacetals; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl, monomethoxytrityl (MMTr); 4,4’-dimethoxytrityl (DMTr); 4,4’,4’’-trimethoxytrityl (TMTr), and those described herein). Amino protecting groups are known to those skilled in the art. Generally, the type of protecting group is not critical, provided that the protecting group is stable to the conditions of any subsequent reaction at other positions of the compound and can be removed at the appropriate time without adversely affecting the remainder of the molecule. Further, after a substantial synthetic reaction is complete, the protecting group may be replaced with another. Clearly, a compound is within the scope of this disclosure if it differs from a compound disclosed herein only in that one or more of the protecting groups of the disclosed compound are replaced with different protecting groups.

[0076] CSA compound The cationic steroid antibacterial (CSA) compound, also referred to as the "CSA compound", "CSA", the CSA molecule or the "seragenin" compound, is a low molecular weight compound synthesized and containing a steroid skeleton to which various charged groups (such as amine groups and cationic groups) are attached. The steroid skeleton can be used to orient an amine or guanidine group on the face or plane of the steroid skeleton. CSA is cationic and amphiphilic based on the functional groups attached to the skeleton of CSA. CSA has a hydrophobic surface and a polycationic surface and is amphiphilic on the surface.

[0077] While not wishing to be bound by any particular theory, the CSA molecules described herein act as antibacterial agents (such as antibacterial, antifungal, and antiviral agents). For example, antibacterial CSA molecules may act as antibacterial agents by binding to the cell membranes of bacteria and other microorganisms and modifying the cell membrane, such as by forming pores that allow the leakage of ions and cytoplasmic substances important for the survival of the microorganism, thereby killing the affected microorganism. Moreover, antibacterial CSA molecules may also act to sensitize bacteria to other antibiotics. For example, using a CSA compound at a concentration of an antibacterial CSA molecule below the corresponding minimum inhibitory concentration (MIC) may make bacteria more susceptible to other antibiotics by disrupting the cell membrane, such as by increasing membrane permeability. The charged cationic groups are hypothesized to be responsible for disrupting the cell membranes of bacteria and conferring antibacterial properties. CSA molecules may have the effect of disrupting the similar membranes or outer membranes of fungi and viruses.

[0078] As background, exemplary CSA compounds and methods for making CSA compounds are described in U.S. Patent Nos. 6,350,738; 6,486,148; 6,767,904; 7,598,234; 7,754,705; 8,691,252; 8,975,310; 9,434,759; 9,527,883; 9,943,614; 10,155,788; 10,227,376; 10,370,403; and 10,626,139, and U.S. Patent Application Publication Nos. 2016 / 0311850 and 2017 / 0210776, which are hereby incorporated by reference herein. One of ordinary skill in the art will recognize the compounds within the general formulas described herein and will understand methods for preparing the compounds in view of the references and examples cited herein. <�

[0079] It should be noted that there might be a small error in the original text where "<�

[0079] " is likely a typo and should probably be "

[0079] ". The translation has been done as accurately as possible based on the provided text.The compounds and compositions disclosed herein are optionally prepared as salts, and when prepared as salts, advantageously the compounds and compositions are cationized when one or more amine groups are protonated. As used herein, the term "salt" is a broad term and should be given its ordinary and customary meaning to one of ordinary skill in the art (not to be limited to a special or customized meaning) and refers to salts of the compounds without limitation. In a plurality of embodiments, this salt is an acid addition salt of the compound. Salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and phosphonic acid. Also, the compound can be reacted with aliphatic or aromatic carboxylic acids or sulfonic acids, organic acids such as sulfinic acids, e.g., formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, or 1,5-naphthalenedisulfonic acid, etc. to obtain salts. Also, the compound can be reacted with a base to form salts such as ammonium salts, alkali metal salts such as lithium salts, sodium salts, or potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, or aluminum salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, etc., and salts with amino acids such as arginine and lysine, or salts of inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. or the like to obtain salts.

[0080] In multiple embodiments, the salt is a hydrochloride salt. In multiple embodiments, the salt is mono hydrochloride, dihydrochloride, trihydrochloride, or tetrahydrochloride. Additional examples of salts include sulfate addition salts, sulfonic acid addition salts, disulfonic acid addition salts, 1,5-naphthalenedisulfonic acid addition salts, sulfate ester salts, and bisulfate ester salts.

[0081] The CSA compounds disclosed herein may have a structure of Formula I, II, or III having a steroid skeleton

Chemical formula

[0082] In multiple embodiments, at least one of R1 to R 18 at least one, preferably at least one of R3, R7, and R 12 at least one has the following urethanyl structure -O-(C=O)-NR 19 R 20 and can have R 19 and R 20 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aminoalkenyl, substituted or unsubstituted aminoalkynyl, and substituted or unsubstituted aminoaryl, provided that at least one of R 19 and R 20 contains an amino group. In an embodiment, R 19 is hydrogen and R 20 is substituted or unsubstituted (C2-C6) aminoalkyl.

[0083] In an embodiment, R18 has the following structure, -R 21 -(C=O)-N-R 22 R 23 and can have, R 21 is selected from being omitted or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl, and R 22 and R 23 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl, provided that 22 and R 23 at least one of them is not hydrogen .

[0084] When the CSA compound has the structure of Formula I, m, n, p, and q are independently 0 or 1.

[0085] When the CSA compound has the structure of Formula I or II, rings A, B, C, and D are independently saturated, or fully or partially unsaturated, provided that at least two of rings A, B, C, and D are saturated.

[0086] When the CSA compound has the structure of Formula I or II, R1~R 18is hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarboxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, alkylaminoalkylaminoalkylamino, aminoalkyl, aryl, arylaminoalkyl, haloalkyl, alkenyl, alkynyl, oxo, a linking group attached to a second steroid, aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, aminoaryluretanyl, aminoalkyloxy, aminoalkylcarboxy, aminoalkyloxyalkyl , aminoalkylaminocarbonyl, aminoalkylcarboxamide, di(alkyl)aminoalkyl, HN—HC(Q5)—(C═O)—O—, HN—HC(Q5)—(C═O)—NH—, azidoalkyloxy, cyanoalkyloxy, PG-HN—HC(Q5)—(C═O)—O—, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy, where Q5 is the side chain of any amino acid (including, for example, the side chain of glycine, such as H), PG is an amino protecting group, and R5, R8, R9, R 10 , R 13 , R 14 and R 17 are independently deleted to complete the valence of the carbon atom at ring A, B, C, or D when the ring is unsaturated; However, R1 to R4, R6, R7, R 11 , R 12 , R 15 , R 16 , and R 18 At least one of R, R and R 12 at least one of which is independently selected from aminoalkyluretanyl, aminoalkenyluretanyl, aminoalkynyluretanyl, and aminoaryluretanyl.

[0087] In the embodiment, R to R 18 is hydrogen, hydroxyl, substituted or unsubstituted (C1-C 22 ) alkyl, substituted or unsubstituted (C1-C 22Hydroxyalkyl, substituted or unsubstituted (C1-C 22 )Alkyloxy-(C1-C 22 )Alkyl, substituted or unsubstituted (C1-C 22 )Alkylcarboxy-(C1-C 22 )Alkyl, substituted or unsubstituted (C1-C 22 )Alkylamino-(C1-C 22 )Alkyl, substituted or unsubstituted (C1-C 22 )Alkylamino-(C1-C 22 )Alkylamino, substituted or unsubstituted (C1-C 22 )Alkylamino-(C1-C 22 )Alkylamino-(C1-C 22 )Alkylamino, substituted or unsubstituted (C1-C 22 )Aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino-(C1-C 22 )Alkyl, substituted or unsubstituted (C1-C 22 )Haloalkyl, substituted or unsubstituted (C2-C6) alkenyl, substituted or unsubstituted (C2-C6) alkynyl, oxo, a linking group bonded to a second steroid, substituted or unsubstituted (C1-C 22 )Aminoalkyluretanil, substituted or unsubstituted (C2-C 22 )Aminoalkenyluretanil, substituted or unsubstituted (C2-C 22 )Aminoalkynyluretanil, and substituted or unsubstituted aminoary luretanil, substituted or unsubstituted (C1-C 22 )Aminoalkyloxy, substituted or unsubstituted (C1-C 22 )Aminoalkylcarboxy, substituted or unsubstituted (C1-C 22 )Aminoalkyloxy-(C1-C 22 )Alkyl, substituted or unsubstituted (C1-C 22 )Aminoalkylaminocarbonyl, substituted or unsubstituted (C1-C 22 )Aminoalkylcarboxamide, substituted or unsubstituted di(C1-C 22 )Alkylamino(C1-C 22Alkyl, H2N-HC(Q5) -(C=O)-O-, H2N-HC(Q5)-(C=O)-NH-, substituted or unsubstituted (C1-C 22 ) azidoalkyloxy, substituted or unsubstituted (C1-C 22 ) cyanoalkyloxy, P.G.-HN-HC(Q5)-(C=O)-O-, substituted or unsubstituted (C1-C 22 ) guanidinoalkyloxy, substituted or unsubstituted (C1-C 22 ) quaternary ammonium alkyl carboxy, and substituted or unsubstituted (C1-C 22 ) guanidinoalkyl carboxy, independently selected from the group consisting of, Q5 is a side chain of an amino acid (including, for example, the side chain of glycine such as H), P.G. is an amino protecting group, and R5, R8, R9, R 10 , R 13 , R 14 and R 17 are independently deleted to complete the valence of the carbon atom at that site when one of rings A, B, C, or D is unsaturated, provided that at least one of R1 to R4, R6, R7, R 11 , R 12 , R 15 , R 16 , and R 18 at least one of, preferably at least one of R3, R7 and R 12 is independently selected from the group consisting of substituted or unsubstituted (C1-C 22 ) aminoalkyl urethanyl, substituted or unsubstituted (C2-C 22 ) aminoalkenyl urethanyl, substituted or unsubstituted (C2-C 22 ) aminoalkynyl urethanyl, and substituted or unsubstituted aminoaryl urethanyl.

[0088] In an embodiment, R1, R2, R4, R5, R6, R8, R9, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 and R 17is independently selected from the group consisting of hydrogen and unsubstituted (C1-C6) alkyl.

[0089] In embodiments, R1, R2, R4, R5, R6, R8, R 10 R 11 R 14 R 16 and R 17 are each hydrogen, and R9 and R 13 are each methyl.

[0090] In embodiments, one or more of rings A, B, C, and D are heterocyclic.

[0091] In embodiments, rings A, B, C, and D are non-heterocyclic.

[0092] In embodiments, the CSA compound is a compound of formula III

Chemical Formula

[0093] In embodiments, at least one, preferably at least two, more preferably all three of R3, R7 and R 12 have the following urethanyl structure, -O-(C=O)-NR 19 R 20 and R 19 and R 20is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aminoalkyl, aminoalkenyl, aminoalkynyl, or aminoaryl, provided that R 19 and R 20 at least one of which contains an amino group. Preferably, R 19 is hydrogen and R 20 is (C2-C6) aminoalkyl.

[0094] In an embodiment, R 18 has the following structure, -R 21 -(C=O)-NR 22 R 23 and R 21 is omitted or is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl such as substituted or unsubstituted (C1-C 10 ) alkyl, substituted or unsubstituted (C2-C 10 ) alkenyl, substituted or unsubstituted (C2-C 10 ) alkynyl, or substituted or unsubstituted (C6 or C 10 ) aryl, and R 22 and R 23 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl. For example, R 22 and R 23 are hydrogen, substituted or unsubstituted (C1-C 24 ) alkyl, substituted or unsubstituted (C2-C 24 ) alkenyl, substituted or unsubstituted (C2-C 24 ) alkynyl, substituted or unsubstituted (C6 or C 10 ) aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 5- to 10-membered heterocyclyl, substituted or unsubstituted (C7-C 13)aralkyl, substituted or unsubstituted 5- to 10-membered heteroaryl-(C1-C6)alkyl, substituted or unsubstituted (C3-C 10 )carbocyclic, substituted or unsubstituted (C4-C 10 )carbocyclic alkyl, and 5- to 10-membered heterocyclic-(C1-C6)alkyl, independently selected from provided that R 21 and R 22 at least one of which is not hydrogen. In some embodiments, R 22 and R 23 are, together with the atom to which R 22 and R 23 are attached, optionally substituted 4- to 10-membered cyclic alkyl ring or 5- to 10-membered heterocyclic ring.

[0095] In an embodiment, when one or two of R3, R7, and R 12 independently have a urethanyl structure as defined herein, one or two of R3, R7, and R 12 are hydrogen, (C1-C 22 )alkyl, (C1-C 22 )hydroxyalkyl, (C1-C 22 )alkyloxy-(C1-C 22 )alkyl, (C1-C 22 )alkylcarboxy-(C1-C 22 )alkyl, (C1-C 22 )alkylamino-(C1-C 22 )alkyl, (C1-C 22 )alkylamino-(C1-C 22 )alkylamino, (C1-C 22 )alkylamino-(C1-C 22 )alkylamino-(C1-C 18 )alkylamino, (C1-C 22 )aminoalkyl, arylamino-(C1-C 22 )alkyl, (C1-C 22 )aminoalkyloxy, (C1-C 22 )aminoalkylcarboxy, (C1-C 22 )aminoalkyloxy-(C1-C 22) alkyl, (C1-C 22 ) aminoalkylamino carbonyl, (C1-C 22 ) aminoalkyl carboxamide, di(C1-C 22 ) alkylaminoalkyl, (C1-C 22 ) guanidinoalkyloxy, (C1-C 22 ) quaternary ammonium alkyl carboxy, and (C1-C 22 ) guanidinoalkyl carboxy, independently selected from the group consisting of.

[0096] Preferably, when one or two of R3, R7, and R 12 have a urethanyl structure as defined herein, one or two of R3, R7, and R 12 are hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C 16 ) alkyloxy-(C1-C5) alkyl, (C1-C 16 ) alkylcarboxy-(C1-C5) alkyl, (C1-C 16 ) alkylamino-(C1-C5) alkyl, (C1-C 16 ) alkylamino(C1-C5) alkylamino, (C1-C 16 ) alkylamino-(C1-C 16 ) alkylamino-(C1-C5) alkylamino, (C1-C 16 ) ami noalkyl, arylamino-(C1-C5) alkyl, (C1-C5) aminoalkyloxy, (C1-C 16 ) aminoalkyloxy-(C1-C5) alkyl, (C1-C5) aminoalkyl carboxy, (C1-C5) aminoalkylamino carbonyl, (C1-C5) aminoalkyl carboxamide, di(C1-C5) alkylamino-(C1-C5) alkyl, (C1-C5) guanidinoalkyloxy, (C1-C 16 ) quaternary ammonium alkyl carboxy, and (C1-C 16 ) guanidinoalkyl carboxy, independently selected from the group consisting of.

[0097] In some embodiments, R3, R7, and R 12 are the same urethanyl group.

[0098] In some embodiments, one or two of R3, R7, and R 12 are aminoalkyloxy.

[0099] In some embodiments, one or two of R3, R7, and R 12 are aminoalkylcarboxy.

[0100] R3, R7 and R 12 Non-limiting examples of CSA compounds in which at least one of is attached to the steroid skeleton by a urethane bond are CSA-255, CSA-256, CSA-257, and salts thereof.

Chemical formula

[0101] Pharmaceutical composition The CSA compounds described herein can be administered alone, but preferably the compounds may be formulated as a pharmaceutical composition (i.e., a formulation). A pharmaceutical composition is any composition that can be administered to a subject in vitro or in vivo or both for the purpose of treating or alleviating a condition. In a preferred embodiment, the pharmaceutical composition may be administered in vivo. The subject may comprise one or more cells or tissues, or organs. In a preferred embodiment, the subject is an animal. In an embodiment, the animal is a mammal. In some embodiments, the mammal is a human or a primate. Mammals include, by way of non-limiting example, any mammal such as cows, pigs, sheep, goats, horses, camels, water buffalo, cats, dogs, rats, mice, and humans.

[0102] "Pharmaceutically acceptable" and "physiologically acceptable" mean a biologically compatible formulation, gas, liquid, or solid, or mixture thereof, which is suitable for one or more routes of administration, in vivo delivery, or contact. A formulation is one in which it does not destroy the activity of the active ingredient of the formulation (e.g., the CSA compound), or induce harmful side effects that far outweigh any prophylactic or therapeutic effect or benefit. It is compatible.

[0103] Depending on the particular method of administration and dosage form, the pharmaceutical composition may be formulated with pharmaceutically acceptable additives such as carriers, solvents, stabilizers, adjuvants, diluents, etc. The pharmaceutical composition can be formulated to achieve a physiologically compatible pH, which can range from about 3 to 11, preferably from about 3 to 7, depending on the formulation and route of administration. In another embodiment, the pH is adjusted to about 5 to 8. The pharmaceutical composition may contain a therapeutically or prophylactically effective amount of at least one compound described herein, together with one or more pharmaceutically acceptable additives.

[0104] The pharmaceutical composition may contain a combination of the compounds described herein and / or a second active ingredient (e.g., an antibacterial or anti-microbial agent) useful for the treatment or prevention of bacterial infections.

[0105] The composition can be formulated, for example, as a coating on a medical device. In an embodiment, the coating is on a medical device.

[0106] Formulations for parenteral or oral administration may be solids, liquid solutions, emulsions, or suspensions. Inhalable formulations for pulmonary administration may be liquids or powders. The pharmaceutical composition can be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration. Another pharmaceutical composition may be formulated as a syrup, cream, ointment, tablet, etc.

[0107] The composition may contain one or more additives. Pharmaceutically acceptable additives are determined in part by the particular composition being administered and the particular method used to administer the composition. There are a wide variety of suitable formulations for pharmaceutical compositions (see, e.g., Remington’s Pharmaceutical Sciences).

[0108] Suitable additives may be carrier molecules that include large, slowly metabolized polymers such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polyamino acids, amino acid copolymers, and inactivated virus particles. Other exemplary additives include antioxidants such as ascorbic acid, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol, wetting or emulsifying agents, pH buffering substances, and the like. Liposomes are pharmaceutically acceptable additives.

[0109] The pharmaceutical composition may be formulated into any form suitable for the intended method of administration. For example, if oral use is intended, tablets, troches, lozenges, aqueous or oily suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain sweetening, flavoring, coloring and preserving agents in order to provide a palatable formulation.

[0110] Pharmaceutically acceptable additives that are particularly suitable for use in combination with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate, disintegrants such as cross-linked polyvinylpyrrolidone, corn starch, or alginic acid, binders such as polyvinylpyrrolidone, starch, gelatin or gum arabic, and lubricants such as magnesium stearate, stearic acid, or talc.

[0111] The tablets do not have to be coated, and may be coated by known techniques including microencapsulation to delay disintegration and absorption in the digestive tract and thereby provide a sustained action over a long period. For example, time-delay substances such as glyceryl monostearate or glyceryl distearate alone or glyceryl distearate and wax may be utilized.

[0112] Formulations for oral use may exist as hard gelatin capsules, in which case the active ingredient is mixed with an inert solid diluent such as, for example, cellulose, lactose, calcium phosphate or kaolin, or may exist as soft gelatin capsules, in which case the active ingredient is mixed with a non-aqueous or oil solvent such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

[0113] The pharmaceutical composition can be formulated as a suspension comprising a CSA compound mixed with at least one pharmaceutically acceptable additive suitable for the manufacture of a suspension.

[0114] The pharmaceutical composition can be formulated as dispersible powders and granules suitable for preparing a suspension by adding suitable additives.

[0115] Additives suitable for use in combination with a suspending agent include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, gum arabic, natural origin phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycethanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), polysaccharides and polysaccharide-like compounds (e.g., dextran sulfate), glycoaminoglycan and glycoaminoglycan-like compounds (e.g., hyaluronic acid), and thickening agents such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspending agent may also contain one or more preservatives such as acetic acid, methyl parahydroxybenzoate, and / or n-propyl, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0116] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture of a vegetable oil such as olive oil or peanut oil and a mineral oil such as liquid paraffin. Suitable emulsifying agents include gums of natural origin such as gum arabic and tragacanth gum, esters or partial esters derived from soybean lectin fatty acids, hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters and ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol or sucrose. Such formulations may also contain emollients, preservatives, flavoring agents or colorants.

[0117] The pharmaceutical composition may be in the form of a sterile injectable preparation such as a sterile aqueous emulsion or an oily suspension. An emulsion or suspension may be prepared according to known techniques using the suitable dispersing or lubricating agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension of a non-toxic parenterally acceptable diluent or solvent such as a 1,2-propanediol solution.

[0118] The sterile injectable preparation may be prepared as a lyophilized powder. Acceptable vehicles and solvents that may be utilized are water, Ringer's solution, and isotonic sodium chloride solution. Further, a sterile fixed oil may be utilized as a solvent or suspending medium. For this purpose, any mild fixed oil containing synthetic mono- or diglycerides may be utilized. Further, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0119] To obtain a stable water-soluble dosage form of the pharmaceutical composition, a pharmaceutically acceptable salt of the compounds described herein may be dissolved in an aqueous solution of an organic or inorganic acid such as 0.3M succinic acid, or more preferably citric acid solution. If a stable salt form cannot be obtained, the compound may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include alcohols, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like at a concentration of about 0-60% of the total volume. In one embodiment, the active compound is dissolved in DMSO and diluted with water.

[0120] The pharmaceutical composition may also be in the form of a solution in which the salt form of the active ingredient is dissolved in a suitable aqueous solvent such as water or isotonic saline or glucose solution. Also contemplated are compounds modified by substituting or adding chemical or biochemical moieties that direct the compound (e.g., increase solubility, bioactivity, affinity, and decrease adverse reactions), such as esterification, glycosylation, pegylation, and complex formation.

[0121] Many therapeutic agents have undesirably short half-lives and / or undesirable toxicities. Thus, the concept of improving half-life and toxicity can be applied to various therapies and fields. However, in order to improve such undesirable characteristics, pharmaceutical compositions can be prepared by complexing a therapeutic agent with a biochemical moiety. Proteins are biochemical moieties that can complex with CSAs for application to a very diverse range of administrations. In some embodiments, one or more CSAs complex with a protein. In some embodiments, one or more CSAs complex with a protein to extend the half-life of the CSA. In other embodiments, one or more CSAs complex with a protein to reduce the toxicity of the CSA. Albumin is a particularly preferred protein that complexes with CSAs. In some embodiments, the albumin is fat-free albumin.

[0122] For a CSA therapeutic agent, a biochemical moiety for complex formation can be added to the pharmaceutical composition in an amount of 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100 equivalents, or in a range bounded by any two of the foregoing numbers, or approximately any of these numbers. In an embodiment, the weight ratio of albumin to CSA is about 18:1 or less, such as about 9:1 or less. In an embodiment, the CSA is coated with albumin.

[0123] Non-biochemical compounds can be added to pharmaceutical compositions to reduce the toxicity of therapeutic agents and / or extend their half-life. Suitable amounts and ratios of additives that can reduce toxicity can be determined by cell assays. For CSA therapeutic agents, compounds that reduce toxicity can be added to the pharmaceutical composition at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100 equivalents, or in a range bounded by any two of the aforementioned numbers, or approximately any of these numbers. In an embodiment, the compound that reduces toxicity is coco amphodiacetic acid such as Miranol® (coco amphodiacetic acid disodium). In an embodiment, the compound that reduces toxicity is an amphoteric surfactant. In an embodiment, the compound that reduces toxicity is a surfactant. In an embodiment, the molar ratio of coco amphodiacetic acid to CSA is about 8:1 to 1:1, preferably about 4:1. In an embodiment, the compound that reduces toxicity is allantoin.

[0124] In an embodiment, the CSA composition is prepared using one or more surfactants. In a particular embodiment, CSA is complexed with one or more poloxamer surfactants It consists of. The poloxamer surfactant is a nonionic triblock copolymer composed of two hydrophilic chain polyoxyethylene (poly(ethylene oxide)) and a central hydrophobic chain polyoxypropylene (poly(propylene oxide)) adjacent to each other. In some embodiments, the poloxamer is a liquid, paste, or flake (solid). Examples of suitable poloxamers include those under the trade names Synperonics, Pluronics, or Kolliphor. In some embodiments, one or more of the poloxamer surfactants in the composition are flake poloxamers. In an embodiment, this one or more poloxamer surfactants in the composition have a molecular weight of about 3600 g / mol in the central hydrophobic chain polyoxypropylene and a polyoxyethylene content of about 70%. In an embodiment, the ratio of one or more poloxamers and CSA is about 50 to 1, about 40 to 1, about 30 to 1, about 20 to 1, about 10 to 1, about 5 to 1, about 1 to 1, about 1 to 10, about 1 to 20, about 1 to 30, about 1 to 40, or about 1 to 50. In an embodiment, the ratio of one or more poloxamers and CSA is 50 to 1, 40 to 1, 30 to 1, 20 to 1, 10 to 1, 5 to 1, 1 to 1, 1 to 10, 1 to 20, 1 to 30, 1 to 40, or 1 to 50. In an embodiment, the ratio of one or more poloxamers and CSA is from about 50 to 1 to about 1 to 50. In an embodiment, the ratio of one or more poloxamers and CSA is from about 30 to 1 to about 3 to 1. In some embodiments, the poloxamer is Pluronics F127.

[0125] The amount of the poloxamer may be based on the weight percentage of the composition. In embodiments, the amount of the poloxamer is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, or approximately any of the foregoing numbers or any range bounded by any two of the foregoing numbers or the formulation. In embodiments, one or more poloxamers are about 10 wt% to about 40 wt% of the formulation administered to the patient. In some embodiments, one or more poloxamers are about 20 wt% to about 30 wt% of the formulation. In embodiments, the formulation contains less than about 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1% CSA. In embodiments, the formulation contains less than about 20 wt% CSA. The poloxamer formulations described above are particularly suitable for treatment methods, coating of devices, preparation of unit dosage forms (i.e., solutions, mouthwashes, injections), etc.

[0126] In embodiments, the compounds described herein may be formulated for oral administration in a liquid-based formulation suitable for poorly soluble compounds. Liquid-based formulations can generally enhance the oral bioavailability of such compounds.

[0127] The pharmaceutical composition may comprise a therapeutically or prophylactically effective amount of a compound described herein, in combination with at least one pharmaceutically acceptable additive selected from the group consisting of medium-chain fatty acids or their propylene glycol esters (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenated castor oil.

[0128] In an embodiment, cyclodextrin may be added as a water solubility enhancer. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, marcil and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. A particularly preferred cyclodextrin solubility enhancer is hydroxypropyl o-cyclodextrin (HPBCD), and hydroxypropyl-o-cyclodextrin may be added to any of the above-described compositions to further improve the water solubility of the compound of the embodiment. In one embodiment, the composition comprises from about 0.1% to about 20% hydroxypropyl-o-cyclodextrin, more preferably from about 1% to about 15% hydroxypropyl-o-cyclodextrin, and most preferably from about 2.5% to about 10% hydroxypropyl-o- contains cyclodextrin. The amount of solubility enhancer utilized will depend on the amount of the compound of the embodiment in the composition.

[0129] Synthesis The methods disclosed herein may be as described below, or as described by variations of these methods. Variations of the methodology include, among other things, temperatures, solvents, reagents, etc. known to those of ordinary skill in the art. Generally, it may be necessary and / or desirable to protect any sensitive or reactive groups of any of the relevant molecules during any of the preparation processes disclosed herein. This may be accomplished by conventional protecting groups such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973), and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), the entire disclosures of both references being incorporated herein by reference. These protecting groups may be removed at convenient subsequent stages using methods known in the art. Synthetic chemical transformations useful for synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, the entire disclosures of both references being incorporated herein by reference. The methods shown and described herein are merely exemplary and are not intended, nor should they be construed, to limit the scope of the claims in any way. Those of ordinary skill in the art can recognize variations of the disclosed syntheses and devise other methods based on the disclosure herein, and all such variations and other methods are within the scope of the claims.

[0130] An exemplary but non-limiting general synthetic scheme for preparing the compounds of Formula I, Formula II, and Formula III is shown in Scheme A. Unless otherwise defined, the variable definitions for Formulas I, II, and / or III are as follows. Scheme A [Chemical]

[0131] Cholic acid (1) is treated with methyl chloroformate in pyridine and dichloromethane to form an intermediate having an acid anhydride at the C24 position, and then a primary or secondary amine R 22 R 23 is treated with NH (such as octylamine) to obtain an intermediate compound having an amide at the C24 position ( 2), or analogs thereof. The amide can be optionally modified and optionally protected before and / or after any of the following steps to obtain a desired functional group at the R 18 position. The intermediate compound (2), or analogs thereof, is treated with an R-chloroformate (such as phenyl chloroformate) in the presence of triethylamine and tetrahydrofuran to obtain an intermediate compound (3) having carbonates at the C3, C7, and C12 positions, or analogs thereof. The intermediate compound (3), or analogs thereof, is treated with an alkylene or arylene diamine (such as an excess of ethylenediamine), and then acidified with hydrochloric acid to obtain an acid addition salt of the CSA compound (such as, CSA-255 HCl).

[0132] In some embodiments, some or all of the foregoing steps can be performed in a one-pot reaction without purifying the intermediate compounds.

[0133] In some embodiments, the intermediate formed by reacting the intermediate compound (3), or analogs thereof, is treated with Tris-Boc to protect the amino group, then purified, and then treated with HCl in dioxane to deprotect the amine and form an HCl acid addition salt.

[0134] When forming the intermediate compound (2) to obtain CSA-256 HCl or CSA-257 HCl, the foregoing reaction can be modified to use decylamine or dodecylamine.

[0135] The HCl acid addition CSA salt can be purified with a base, optionally neutralized, and then separated (e.g., by two-phase liquid separation and subsequent evaporation of the organic solvent) to obtain a purified free base. The free base can be used as is, or can be acidified with any desired acid to form an acid addition salt.

[0136] Exemplary acid addition salts are salts of 1,5-naphthalenedisulfonic acid (1,5-NDSA salts, e.g., di-addition salts), which are highly poorly soluble and thus useful as coatings, such as for coatings of implantable medical devices. In some cases, the NDSA salt is ground into submicron-sized particles and added to the coating in particulate form. The NDSA salt does not dissolve in ethylene oxide, which is commonly used to sterilize medical devices, and can thus remain as a stable coating after multiple sterilization cycles.

[0137] Ionizing the CSA compound, such as by exchanging the NDSA moiety with other anions such as chloride ions using HCl, sodium chloride, etc., results in a primary release rate equation and can increase the release rate under acidic conditions.

[0138] An advantage of the disclosed CSA compounds is that these compounds are thermally stable and do not polymerize or form crosslinked urethanes even at high temperatures.

Example

[0139] Example The antibacterial activity of CSA-255 was determined in comparison with CSA-44, a CSA compound known to have very high antibacterial activity compared to other CSAs. The microorganisms used in the comparative study were methicillin resistant Staphylococcus aureus (MRSA) BAA-41 and Pseudomonas aeruginosa (PA01 47085). The measured minimum inhibitory concentration (MIC) is listed in Table 1.

Table 1

[0140] Unexpectedly, the CSA compounds within the scope of the present invention have been known and used for many years and have antibacterial activity identical or similar to that of the CSA that has been used, but the bond between the active amino group and the sterol skeleton is quite different.

[0141] The present invention can be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments should be considered in all respects only as illustrative and not restrictive. Accordingly, the scope of the present invention is shown not by the above description but by the appended claims. All modifications falling within the meaning and scope of equivalence of the claims are intended to be embraced within the scope of the claims.

Claims

1. The structure of formula III, wherein 【Chemical 1】 R3, R7, and R12 are the same urethanyl group selected from the group consisting of aminoalkyl urethanyl, aminoalkenyl urethanyl, aminoalkynyl urethanyl, and aminoaryl urethanyl; R18 is hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkyloxyalkyl, alkylcarboxyalkyl, amide, alkylaminoalkyl, alkylaminoalkylamino, alkylaminoalkylaminoalkylamino, aminoalkyl, aryl, arylaminoalkyl, haloalkyl, alkenyl, alkynyl, oxo, a linking group bonded to a second steroid, aminoalkyloxy, aminoalkylcarboxy, aminoalkyloxyalkyl, aminoalkylaminocarbonyl, aminoalkylcarboxamide, di(alkyl)aminoalkyl, H2N-HC(Q5)-(C=O)-O-, H2N-HC(Q5)-(C=O)-NH-, azidoalkyloxy, cyanoalkyloxy, P.G.-HN-HC(Q5)-(C=O)-O-, guanidinoalkyloxy, quaternary ammonium alkylcarboxy, and guanidinoalkylcarboxy, where Q5 is the side chain of any amino acid and P.G. is an amino protecting group, a cationic steroid antibacterial (CSA) compound having the structure, or a salt thereof.

2. R3, R7 and R12 are (C １ ~C ２２ )aminoalkyl urethanyl, (C ２ ~C ２ ２ ), an aminoalkenyl urethanyl, (C ２ ~C ２２ ), an aminoalkynyl urethanyl, and an aminoaryl urethanyl, which is the same urethanyl group selected from the group consisting of: the CSA compound according to claim 1.

3. R3, R7, and R12 have the following urethanyl structure -O-(C=O)-NR １９ R ２０ and R １９ and R ２０ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aminoalkyl, aminoalkenyl, aminoalkynyl, and aminoaryl, provided that at least one of R １９ and R ２０ contains an amino group. a CSA compound according to claim 1 or 2.

4. R １９ is hydrogen, and R ２０ is (C ２ ~C ６ ) aminoalkyl, the CSA compound according to claim 3.

5. R １８ has the following structure, -R ２１ -(C=O)-N-R ２２ R ２３ and R ２１ is omitted or selected from alkyl, alkenyl, alkynyl, and aryl, and R ２２ and R ２３ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and aryl, provided that at least one of R ２２ and R ２３ is not hydrogen a CSA compound according to any one of claims 1 to 4.

6. R ２１ is omitted or is selected from (C １ ~C １０ )alkyl, (C ２ ~C １０ )alkenyl, (C ２ ~C １０ )alkynyl, and (C ６ or C １０ )aryl, and R ２２ and R ２３ are independently selected from hydrogen, (C １ ~C ２４ )alkyl, (C ２ ~C ２４ )alkenyl, (C ２ ~C ２４ )alkynyl, (C ６ or C １０ )aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, (C ７ ~C １３ )aralkyl, 5- to 10-membered heteroaryl-(C １ ~C ６ )alkyl, (C ３ ~C １０ )carbocyclic, (C ４ ~C １０ )carbocyclic alkyl, and 5- to 10-membered heterocyclyl-(C １ ~C ６ )alkyl, provided that at least one of R ２１ and R ２２ is not hydrogen, the CSA compound according to claim 5.

7. The CSA compound is selected from CSA-255, CSA-256, CSA-257, CSA-258, 【Chemical 2】 and salts thereof, a CSA compound according to any one of claims 1 to 6.

8. A pharmaceutical composition comprising a CSA compound according to any one of claims 1 to 7 and a pharmaceutically acceptable additive selected from carriers, solvents, stabilizers, adjuvants, and diluents.

9. Treating cholic acid with methyl chloroformate in pyridine and dichloromethane to form an intermediate having an acid anhydride at the C24 position for the purpose of forming a first intermediate compound. The first intermediate compound is treated with a primary or secondary amine R ２２ R ２３ NH (R22 and R23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and aryl, provided that at least one of R22 and R23 is not hydrogen) to obtain a second intermediate compound having an amide at the C24 position. Optionally modify and / or protect the amide of the second intermediate compound to obtain a desired functional group at the R １８ position, Treating the second intermediate compound or analogs thereof with an R-chloroformate in the presence of triethylamine and tetrahydrofuran to obtain a third intermediate compound having carbonates at the C3, C7 and C12 positions, and treating the third intermediate compound with an alkylene or arylenediamine to obtain a CSA compound or these intermediates, including A method for producing a CSA compound according to any one of claims 1 to 7.

10. The method according to claim 9, wherein the primary or secondary amine R22R23NH is octylamine.

11. The method according to claim 9 or 10, wherein the R-chloroformate is phenyl chloroformate.

12. The method according to any one of claims 9 to 11, wherein the alkylene or arylenediamine contains an excess amount of ethylenediamine.

13. The method according to any one of claims 9 to 12, further comprising acidifying the CSA compound or these intermediates with an acid to obtain an acid addition salt of the CSA compound.

14. The method according to claim 13, wherein the acid is hydrochloric acid.

15. The method according to claim 13 or 14, further comprising treating the acid addition salt of the CSA compound with a base and obtaining the free base of the CSA compound.

16. The method according to claim 15, further comprising acidifying the free base of the CSA compound to form a second acid addition salt of the CSA compound.

17. The method according to claim 16, wherein the second acid addition salt of the CSA compound is a 1,5-naphthalenedisulfonic acid di-addition salt.

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